The tight junction protein claudin 6 (CLDN6) is emerging as a significant therapeutic target in oncology, with multiple novel treatment approaches showing encouraging early clinical results in solid tumors. Located on chromosome 16p13.3, CLDN6 is uniquely positioned as a cancer target due to its minimal expression in normal adult tissue while being prominently expressed in various tumor types.
Early Success with Antibody-Drug Conjugates
DS-9606, a novel antibody-drug conjugate comprising a humanized anti-CLDN6 monoclonal antibody with a cleavable linker to a modified pyrrolobenzodiazepine payload, has demonstrated promising activity in early trials. In a phase 1 study involving 53 patients with various solid tumors, the agent showed particular efficacy at the 0.150-mg/kg dose, with three of twelve patients achieving confirmed objective responses.
The safety profile has been manageable, with no dose-limiting toxicities reported. Common treatment-emergent adverse effects included nausea (18.9%), fatigue (18.9%), and anemia (17.0%), with notably no cases of pneumonitis observed during the study period.
TORL-1-23, another CLDN6-directed antibody-drug conjugate, has shown even more impressive results. In CLDN6-positive platinum-resistant ovarian cancer, patients treated with 2.4 mg/kg achieved a 50% objective response rate, with responses lasting approximately 22 weeks. The 3.0 mg/kg dose group demonstrated a 42% response rate with extended duration of response reaching about 30 weeks.
Innovative CAR T-Cell Approach
A groundbreaking combination strategy using BNT211, which pairs CLDN6 CAR T-cell therapy with a CAR vaccine, has yielded significant results in relapsed/refractory CLDN6-positive solid tumors. The overall response rate reached 32.8% across all patients, but notably improved to 51.5% in patients receiving optimal dosing with complete lymphodepletion and the CAR vaccine combination.
Particularly encouraging results were seen in specific cancer types:
- Ovarian cancer patients showed a 58.3% response rate with optimal dosing
- Testicular cancer patients achieved a 41.7% response rate under similar conditions
Safety Considerations and Future Directions
While these therapies show promise, careful attention to safety profiles remains crucial. The CAR T-cell approach, while effective, has shown significant toxicity with 91% of patients experiencing grade 3 or higher treatment-emergent adverse events. However, the antibody-drug conjugates have demonstrated more manageable safety profiles.
The development of these CLDN6-targeted therapies represents a significant advance in oncology, particularly for difficult-to-treat solid tumors. Multiple clinical trials are ongoing, with plans for expansion into additional CLDN6-positive cancer types, including non-small cell lung cancer and other solid tumors.
Dr. Gottfried E. Konecny of UCLA Health notes, "TORL-1-23 has a very high specificity for CLDN6," highlighting the precision of these new therapeutic approaches. This specificity, combined with the encouraging efficacy data, suggests that CLDN6-targeted therapies could become an important addition to the cancer treatment arsenal.
